p38 mitogen-activated protein (MAP) kinase (p38α/Mpk2/RK/SAPK2a/CSBP) (hereinafter referred to as “p38 MAP kinase”) was cloned as an enzyme which induces tyrosine phosphorylation in monocyte after stimulation with lipopolysaccharide (LPS) (Nature, 372, 739 (1994)), and is activated by various extracellular stimuli [physical stimuli (osmotic shock, heat shock, UV irradiation, and so forth), chemical stimuli (endotoxin, hydrogen peroxide, arsenic trioxide, an inflammatory cytokine, a growth factor, and so forth), and so on]. Also, since p38 MAP kinase is involved in the production of an inflammatory cytokine (such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, IL-8, and so forth), a chemokine, and so on, an association between the activation of this enzyme and diseases is strongly suggested. Therefore, an improvement effect on various disease symptoms typified by inflammatory diseases is expected by suppression of p38 MAP kinase activation.
Accordingly, a p38 MAP kinase inhibitor is expected to be useful in prevention and/or treatment of those diseases that are supposedly caused or deteriorated by abnormal production of cytokines including inflammatory cytokine or chemokine, or by over response thereto, namely cytokine-mediated diseases such as various inflammatory diseases [for example, inflammation, dermatitis, atopic dermatitis, hepatitis, nephritis, glomerulonephritis, pancreatitis, psoriasis, gout, Addison's disease, arthritis (e.g., rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.), inflammatory ocular diseases, inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), etc.), inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis, etc.), allergic diseases (e.g., allergic dermatitis, allergic rhinitis, etc.), autoimmune disease, autoimmune hemolytic anemia, systemic lupus erythematosus, rheumatism, Castleman's disease, immune rejection accompanying transplantation (e.g., graft versus host reaction, etc.), and so forth], central nervous system disorders [for example, central neuropathy (e.g., cerebrovascular disease such as cerebral hemorrhage and cerebral infarction, head trauma, spinal cord injury, cerebral edema, multiple sclerosis, etc.), neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), AIDS encephalopathy, etc.), meningitis, Creutzfeldt-Jakob syndrome, and so forth], respiratory diseases [for example, asthma, chronic obstructive pulmonary disease (COPD), and so forth], cardiovascular diseases [for example, angina, heart failure (e.g., congestive heart failure, acute heart failure, chronic heart failure, etc.), myocardial infarction (e.g., acute myocardial infarction, myocardial infarction prognosis, etc.), atrial myxoma, arteriosclerosis, hypertension, dialysis-induced hypotension, thrombosis, disseminated intravascular coagulation (DIC), reperfusion injury, restenosis after percutaneous transluminal coronary angioplasty (PTCA), and so forth], urinary diseases [for example, renal failure, and so forth], metabolic diseases or endocrine diseases [for example, diabetes, and so forth], bone diseases [for example, osteoporosis, and so forth], cancerous diseases [for example, malignant tumor (e.g., tumor growth and metastasis, etc.), multiple myeloma, plasma cell leukemia, carcinemia, and so forth], and infectious diseases [for example, viral infection (e.g., cytomegalovirus infection, influenza virus infection, herpes virus infection, corona virus infection, etc.), cachexia associated with infections, cachexia caused by acquired immune deficiency syndrome (AIDS), toxemia (e.g., sepsis, septic shock, endotoxin shock, gram negative bacterial sepsis, toxic shock syndrome, severe acute respiratory syndrome (SARS) accompanying virus infection, etc.), and so forth], and so on.
On the other hand, WO 01/096308 discloses that the compounds represented by general formula (W), the salts thereof, or the hydrate thereof have an inhibitory effect on AMPA receptor and/or kainic acid receptor:

wherein QW represents NH, O or S;
R1W, R2W, R3W, R4W and R5W represent, samely or differently, hydrogen atom, halogen atom, C1-6 alkyl, or —XW-AW (wherein XW represents a bond, an optionally substituted C1-6 alkylene, an optionally substituted C2-6 alkenylene, an optionally substituted C2-6 alkynylene, —O—, —S—, —CO—, —SO—, —SO2—, —N(R6W)—, —N(R7W)—CO—, —CO—N(R8W)—, —N(R9W)—CH2—, —CH2—N(R10W)—, —CH2—CO—, —CO—CH2—, —N(R11W)—S(O)mW—, —S(O)nW—N(R12W)—, —CH2—S(O)pW—, —S(O)qW—CH2—, —CH2—O—, —O—CH2—, —N(R13W)—CO—N(R14W)—, or —N(R15W)—CS—N(R16W)— (wherein R6W, R7W, R8W, R9W, R10W, R11W, R12W, R13W, R14W, R15W and R16W represent hydrogen atom, C1-6 alkyl or C1-6 alkoxy; mW, nW, pW and qW each independently represents 0 or an integer of 1 or 2); AW represents C3-8 cycloalkyl, C3-8 cycloalkenyl, a non-aromatic 5- to 14-membered hetero ring, an aromatic C6-14 hydrocarbon ring or an aromatic 5- to 14-membered hetero ring, and these rings are optionally substituted by substituent respectively);
with the proviso that, three of R1W, R2W, R3W, R4W and R5W, samely or differently, represent —XW-AW and residual two always represent hydrogen atom, halogen atom, or C1-6 alkyl;
provided that in the above-mentioned definition, the cases where (1) QW is O; R1W and R5W are hydrogen atom; and R2W, R3W and R4W are phenyl groups, (2) QW is O; R1W and R4W are hydrogen atom; and R2W, R3W and R5W are phenyl groups, and (3) QW is O; R1W and R2W are hydrogen atom; and R3W, R4W and R5W are phenyl groups, are excluded.
Also, Japanese Publication Toku-Kai-Syo 60-58981 discloses that 1,3-thiazole derivatives represented by general formula (Y) or the salts thereof have inhibitory effects on pain, fever, inflammation, ulcer, thromboxane A2 (TXA2) synthesis, and platelet aggregation:

wherein R1Y represents cycloalkyl, cyclic amino, amino having 1 or 2 substituent(s) selected from the group consisting of lower alkyl, phenyl, acetyl, and lower alkoxycarbonylacetyl, alkyl which may be substituted by hydroxyl, carboxyl or lower alkoxycarbonyl, or phenyl which may be substituted by carboxyl, 2-carboxyetenyl or 2-carboxy-1-propenyl;
R2Y represents pyridyl which may be substituted by lower alkyl;
R3Y represents lower alkoxy, lower alkyl, hydroxyl, halogen, or phenyl which may be substituted by methylenedioxy.
Moreover, WO 00/064894 discloses that the compounds represented by general formula (Z) which may be N-oxidated or the salts thereof are useful as p38 MAP kinase inhibitors:

wherein R1Z represents hydrogen atom, an optionally substituted hydrocarbon, an optionally substituted hetero ring, an optionally substituted amino or acyl;
R2Z represents an optionally substituted aromatic group;
R3Z represents hydrogen atom, an optionally substituted pyridyl, or an optionally substituted aromatic hydrocarbon;
XZ represents oxygen atom or an optionally oxidized sulfur atom;
YZ represents a bond, oxygen atom, an optionally oxidized sulfur atom, or NR4Z (wherein R4Z represents hydrogen atom, an optionally substituted hydrocarbon, or acyl);
ZZ represents a bond or a bivalent aliphatic hydrocarbon which may have a substituent(s).
Furthermore, WO 03/043988 discloses that the compounds represented by general formula (A) or the non-toxic salts thereof are useful as p38 MAP kinase inhibitors:

wherein AA represents a C5-10 mono- or poly-cyclic carbon ring, or a 5- to 10-membered mono- or poly-cyclic hetero ring containing 1 to 5 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 sulfur atom;
R1A represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen atom, (5) —OR4A, (6) —NR5AR6A, (7) —NR7ACOR8A, (8) —CONR9AR10A, (9) —COOR11A, (10) —SO2NR12AR13A, (11) —NR14ASO2R15A, (12) —SR16A, (13) —S(O)R17A, (14) —SO2R18A, (15) —NR22ACOOR23A, (16) —NR24ACONR25AR26A, (17) —COR27A, (18) nitro, (19) cyano, (20) trifluoromethyl, (21) trifluoromethoxy, (22) Cyc1A, or the like;
R4A-R18A and R22A-R27A each independently represent a hydrogen atom, C1-8 alkyl Cyc1A, or the like;
Cyc1A represents a C5-10 mono- or poly-cyclic carbon ring or the like (with the proviso that, the carbon ring or the like may be substituted with one to five R48A(s));
R48A represents C1-8 alkyl, halogen atom, nitro, cyano, or the like;
R2A represents C1-8 alkyl, —OR20A, —NR64AR65A, —COOR66A, —CONR67AR68A, —NR69ACOR70A, —SO2R71A, —SO2NR72AR73A, —NR74ASO2R75A, —NR76ACOOR77A, Cyc2A or the like;
R20A and R64A-R77A each independently represents hydrogen atom, C1-8 alkyl, Cyc2A, or the like;
Cyc2A represents a C5-6 mono-cyclic carbon ring or the like (with the proviso that, the carbon ring or the like may be substituted by one to five substituent(s) such as C1-8 alkoxy, halogen atom or the like);
GA and JA each independently represents a carbon, nitrogen, oxygen, or sulfur atom;
EA represents C1-4 alkylene, —O—, —S—, or the like (with the proviso that, the C1-4 alkylene may be substituted by one to five substituent(s) such as C1-8 alkoxy, halogen atom, hydroxy, or the like);
BA represents a C5-10 mono- or poly-cyclic carbon ring, or a 5- to 10-membered mono- or poly-cyclic hetero ring containing 1 to 4 nitrogen atom(s), 1 to 2 oxygen atom(s) and/or 1 sulfur atom;
R3A represents C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen atom, —OR81A, —NR82AR83A, —NR84ACOR85A, —CONR86AR87A, —COOR88A, —SO2NR89AR90A, —NR91ASO2R92A, —SR93A, —S(O)R94A, —SO2R95A, —NR96ACOOR97A, —NR98ACONR99AR100A, —OCONR101AR102A, nitro, cyano, trifluoromethyl, trifluoromethoxy, Cyc4A, or the like;
R81A-R102A each independently represents hydrogen atom, C1-8 alkyl, Cyc4A, or the like;
Cyc4A represents a C5-10 mono- or poly-cyclic carbon ring or the like (with the proviso that, the carbon ring or the like may be substituted by one to five substituent(s) such as C1-8 alkoxy, halogen atom or the like);
mA represents 0 or an integer of 1 to 5;
nA represents 0 or an integer of 1 to 7;
iA represents 0 or an integer of 1 to 12, with the proviso that, only necessary part of the meanings of the symbols in the formula were excerpted.
And more, WO 01/030778 discloses that the compounds represented by general formula (B), the pharmaceutically-acceptable cleavable esters thereof, or the acid-addition salts thereof are useful as p38 MAP kinase inhibitors:

wherein ZB represents N or CH;
XB represents —NR6B—YB—, —O— or —S— (wherein R6B represents hydrogen atom, C1-4 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-3 alkyl, C6-18 aryl, C3-18 heteroaryl, C7-19 aralkyl, or C4-19 heteroaralkyl, and —YB— represents C1-4 alkylene or a bond);
R2B represents phenyl which may be substituted by one or more substituent(s), the substituent(s) are selected from the group consisting of halo, trifluoromethyl, cyano, amide, thioamide, carboxylate, thiocarboxylate, C1-4 alkoxy, C1-4 alkyl, or amino which may be substituted by one or two C1-4 alkyl;
R3B represents hydrogen atom, C1-10 alkyl, C3-10 cycloalkyl, C3-18 heterocycloalkyl, C6-18 aryl, or C3-18 heteroaryl, and each may have up to four substituent(s) selected from the group consisting of C1-4 alkyl, halogen atom, halogen-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, or amino which may be substituted by one or two C1-4 alkyl, or 5- to 7-membered nitrogenous hetero ring optionally containing further hetero atom selected from oxygen, sulfur or nitrogen atom;
R4B represents C6-18 aryl, C3-18 heteroaryl or C3-12 cycloalkyl, substituted by up to four substituent(s) selected from the group consisting of C1-4 alkyl, halogen atom, halogen-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, or optionally mono- or di-C1-C4alkyl substituted amino, or by N-heterocyclyl containing from 5 to 7 ring atoms and optionally containing a further hetero atom selected from O, S or N.